Genetic Variant HMGA2:c.*221T>C (chr12-65915135-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001300919.1(HMGA2):c.*221T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,613,640 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 3 hom. )

Consequence

HMGA2
NM_001300919.1 3_prime_UTR

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.782

Variant links:

Genes affected

HMGA2 (HGNC:5009): (high mobility group AT-hook 2) This gene encodes a protein that belongs to the non-histone chromosomal high mobility group (HMG) protein family. HMG proteins function as architectural factors and are essential components of the enhancesome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. Identification of the deletion, amplification, and rearrangement of this gene that are associated with myxoid liposarcoma suggests a role in adipogenesis and mesenchymal differentiation. A gene knock out study of the mouse counterpart demonstrated that this gene is involved in diet-induced obesity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

HMGA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 12-65915135-T-C is Benign according to our data. Variant chr12-65915135-T-C is described in ClinVar as [Benign]. Clinvar id is 3033396.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000683 (104/152332) while in subpopulation EAS AF= 0.0195 (101/5186). AF 95% confidence interval is 0.0164. There are 1 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HMGA2	NM_003483.6 link	c.250-36248T>C	intron_variant	Intron 3 of 4	ENST00000403681.7	NP_003474.1	P52926-1
HMGA2	NM_001300919.1 link	c.*221T>C	3_prime_UTR_variant	Exon 4 of 4		NP_001287848.1	Q1M183F5H6H0
HMGA2	NM_003484.1 link	c.*5T>C	3_prime_UTR_variant	Exon 4 of 4		NP_003475.1	P52926-2
HMGA2	NM_001300918.1 link	c.250-36248T>C	intron_variant	Intron 3 of 4		NP_001287847.1	F5H2A4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGA2	ENST00000403681.7 link	c.250-36248T>C		intron_variant	Intron 3 of 4	1	NM_003483.6	ENSP00000384026.2		P52926-1

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0194

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00182

AC:

458

AN:

251322

Hom.:

AF XY:

0.00163

AC XY:

222

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0241

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000477

AC:

697

AN:

1461308

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

322

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0160

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152332

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0195

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.000824

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HMGA2-related disorder

Benign:1

Jun 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.0

DANN

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over